David Jamil Hadad

Population Pharmacokinetics of Levofloxacin, Gatifloxacin, and Moxifloxacin in Adults with Pulmonary Tuberculosis

ABSTRACT The objective of this study was to determine the population pharmacokinetic parameters of levofloxacin, gatifloxacin, and moxifloxacin following multiple oral doses. Twenty-nine patients with tuberculosis at the University Hospital in Vitória, Brazil, participated. Subjects received multiple doses of one drug (levofloxacin, 1,000 mg daily, or gatifloxacin or moxifloxacin, 400 mg daily) as part of a 7-day study of early bactericidal activity. Serum samples were collected over 24 h after the fifth dose and assayed using validated high-performance liquid chromatography assays. Concentration-time data were analyzed using noncompartmental, compartmental, and population methods. The three drugs were well tolerated. Levofloxacin produced the highest maximum plasma concentrations (median, 15.55 μg/ml; gatifloxacin, 4.75 μg/ml; moxifloxacin, 6.13 μg/ml), largest volume of distribution (median, 81 liters; gatifloxacin, 79 liters; moxifloxacin, 63 liters), and longest elimination half-life (median, 7.4 h; gatifloxacin, 5.0 h; moxifloxacin, 6.5 h). A one-compartment model, with or without weight as a covariate, adequately described the data. Postmodeling simulations using median population parameter estimates closely approximated the median values from the original data. Area under the concentration-time curve/MIC ratios for free drug were high. All three quinolones showed favorable pharmacokinetic and pharmacodynamic indices, with the most favorable results in this population being seen with levofloxacin at the comparative doses used.

Early and Extended Early Bactericidal Activity of Linezolid in Pulmonary Tuberculosis

RATIONALEnLinezolid, the first oxazolidinone approved for clinical use, has effective in vitro and promising in vivo activity against Mycobacterium tuberculosis.nnnOBJECTIVESnTo evaluate the early and extended early bactericidal activity of linezolid in patients with pulmonary tuberculosis.nnnMETHODSnRandomized open label trial. Thirty patients with newly diagnosed smear-positive pulmonary tuberculosis (10 per arm) were assigned to receive isoniazid (300 mg daily) and linezolid (600 mg twice daily or 600 mg once daily) for 7 days. Sputum for quantitative culture was collected for 2 days before and then daily during 7 days of study drug administration. Bactericidal activity was estimated by measuring the decline in bacilli during the first 2 days (early bactericidal activity) and the last 5 days of study drug administration (extended early bactericidal activity).nnnMEASUREMENTS AND MAIN RESULTSnThe mean early bactericidal activity of isoniazid (0.67 log10 cfu/ml/d) was greater than that of linezolid twice and once daily (0.26 and 0.18 log10 cfu/ml/d, respectively). The extended early bactericidal activity of linezolid between Days 2 and 7 was minimal.nnnCONCLUSIONSnLinezolid has modest early bactericidal activity against rapidly dividing tubercle bacilli in patients with cavitary pulmonary tuberculosis during the first 2 days of administration, but little extended early bactericidal activity. Clinical trial registered with www.clinicaltrials.gov (NCT00396084).

Cavitary Disease and Quantitative Sputum Bacillary Load in Cases of Pulmonary Tuberculosis

ABSTRACT We examined sputum bacterial loads in adults with newly diagnosed tuberculosis using quantitative culture and time-until-positive (DTP) culture in BACTEC 460. Patients with cavitary disease had higher CFU levels than those without cavities and shorter DTPs. Within radiographic strata of moderately and far advanced tuberculosis, higher CFU counts were associated with cavitary disease.

Shortening Treatment in Adults with Noncavitary Tuberculosis and 2-Month Culture Conversion

RATIONALEnCavitary disease and delayed culture conversion have been associated with relapse. Combining patient characteristics and measures of bacteriologic response might allow treatment shortening with current drugs in some patients.nnnOBJECTIVESnTo assess whether treatment could be shortened from 6 to 4 months in patients with noncavitary tuberculosis whose sputum cultures converted to negative after 2 months.nnnMETHODSnThis study was a randomized, open-label equivalence trial. HIV-uninfected adults with noncavitary tuberculosis were treated daily with isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by 2 months of isoniazid and rifampin. After 4 months, patients with drug-susceptible TB whose sputum cultures on solid media were negative after 8 weeks of treatment were randomly assigned to continue treatment for 2 more months or to stop treatment. Patients were followed for relapse for 30 months after beginning treatment.nnnMEASUREMENTS AND MAIN RESULTSnEnrollment was stopped by the safety monitoring committee after 394 patients were enrolled due to apparent increased risk for relapse in the 4-month arm. A total of 370 patients were eligible for per protocol analysis. Thirteen patients in the 4-month arm relapsed, compared with three subjects in the 6-month arm (7.0 vs. 1.6%; risk difference, 0.054; 95% confidence interval with Hauck-Anderson correction, 0.01-0.10).nnnCONCLUSIONnShortening treatment from 6 to 4 months in adults with noncavitary disease and culture conversion after 2 months using current drugs resulted in a greater relapse rate. The combination of noncavitary disease and 2-month culture conversion was insufficient to identify patients with decreased risk for relapse.

Epidemic of surgical-site infections by a single clone of rapidly growing mycobacteria in Brazil

AIMnOur aim is to investigate if the clusters of postsurgical mycobacterial infections, reported between 2004 and 2008 in seven geographically distant states in Brazil, were caused by a single mycobacterial strain.nnnMATERIALS & METHODSnAvailable information from 929 surgical patients was obtained from local health authorities. A total of 152 isolates from surgical patients were identified by PCR restriction enzyme analysis of the hsp65 gene (PRA-hsp65) and sequencing of the rpoB gene. Isolates were typed by pulsed-field gel electrophoresis (PFGE) using two restriction enzymes, DraI and AseI. A total of 15 isolates not related to surgical cases were analyzed for comparison.nnnRESULTSnAll isolates were identified as Mycobacterium abscessus ssp. massiliense. Isolates from surgical patients and one sputum isolate grouped in a single PFGE cluster, composed of two closely related patterns, with one band difference. A total of 14 other isolates unrelated to surgical cases showed distinctive PFGE patterns.nnnCONCLUSIONnA particular strain of M. abscessus ssp. massiliense was associated with a prolonged epidemic of postsurgical infections in seven Brazilian states, suggesting that this strain may be distributed in Brazilian territory and better adapted to cause surgical-site infections.

Smoking and 2-month culture conversion during anti-tuberculosis treatment.

OBJECTIVEnTo investigate risk factors for delayed sputum culture conversion to negative during anti-tuberculosis treatment, with an emphasis on smoking.nnnDESIGNnNested case-control study of adults with non-cavitary, culture-confirmed pulmonary tuberculosis (TB) participating in an anti-tuberculosis treatment trial in Brazil. A case of delayed culture conversion was a patient who remained culture-positive after 2 months of treatment. Odds ratios with 95% confidence intervals were calculated.nnnRESULTSnFifty-three cases and 240 control patients were analyzed. Smokers had three-fold greater odds of remaining culture-positive after 2 months of treatment (P = 0.007) than non-smokers, while smokers and ex-smokers who smoked >20 cigarettes a day had two-fold greater odds of remaining culture-positive after 2 months of treatment (P = 0.045).nnnCONCLUSIONnCigarette smoking adversely affects culture conversion during anti-tuberculosis treatment. Support for smoking cessation should be considered to improve outcomes in TB control programs.

Population Pharmacokinetics of Linezolid in Adults with Pulmonary Tuberculosis

ABSTRACT Nineteen adults with pulmonary tuberculosis received linezolid (600 mg) once or twice daily in an early bactericidal activity trial. A one-compartment population model produced median values for the absorption rate constant, volume of distribution, and elimination rate constant of 1.5 h−1, 29.6 liters, and 0.25 h−1 (once daily) and 2.7 h−1, 32.1 liters, and 0.15 h−1 (twice daily). Linezolid administered twice daily produced higher values for free drug area under the concentration-time curve (AUC)/MIC and time above MIC. Both regimens achieved free AUC/MIC ratios > 100. Median times above the MIC for free drug were 100% (twice daily) and 63% (once daily).

Immune reconstitution syndrome in patients treated for HIV and tuberculosis in Rio de Janeiro

We made a retrospective longitudinal study from January 2000 to January 2003 to examine cases of immune reconstitution syndrome (IRS) and its incidence rate in tuberculosis (TB)-human immunodeficiency virus (HIV) co-infected patients. The incidence rate (IR) was calculated using a Poisson regression. The confidence interval (CI) that was stipulated was 95%. IRS occurred in 10/84 HIV and TB-positive patients; nine of them were on highly active anti-retroviral therapy (HAART) during a mean of 61.7 (+/- 59) days following the introduction of antiretrovirals. Lymph-node enlargement was the sole clinical manifestation. CD4 counts were <100 cells/mm(3)in 50% of the patients, at the time of TB diagnosis. All but two patients were treated with prednisone, and recovered from TB within a mean of 91 days (+/- 30 days). One relapse of TB was observed, but there were no IRS-related deaths. The incidence rate was higher (IR=11.18; CI, 1.41-88.76) in patients that had superficial lymph node enlargement at the moment of TB diagnosis (not associated with TB), extrapulmonary TB (IR=1.97; CI, 0.44-8.79), were antiretroviral naive (IR=1.85; CI, 0.48-7.16), and CD4 counts <100 cells/mm(3) (IR=1.50; CI, 0.40-5.59), although with a wide CI. IRS was frequent in our sample, occurred more frequently in HIV-naive patients with lymph-node enlargement and extrapulmonary TB. No cases of new pulmonary lesions or worsening of pulmonary infiltrates were observed.

Efeitos adversos causados pelo novo esquema de tratamento da tuberculose preconizado pelo Ministério da Saúde do Brasil

OBJECTIVEnTo determine the principal adverse effects of the tuberculosis treatment regimen recommended by the Brazilian Ministry of Health.nnnMETHODSnA prospective descriptive study involving 79 tuberculosis patients treated at the Clinical Research Center of the Cassiano Antonio Moraes University Hospital, in the city of Vitória, Brazil, between 2003 and 2006. The treatment regimen consisted of isoniazid, rifampicin, pyrazinamide and ethambutol for four months, followed by rifampicin and isoniazid for two months. During the treatment period, the patients were clinically evaluated every week and had a monthly medical visit.nnnRESULTSnThe overall incidence of adverse effects was 83.54%. Articular/bone/muscle involvement was the most common, followed by skin involvement (24.94% and 22.09%, respectively). Adverse effects were more common in the second month of treatment (41.59%). Modification of the treatment regimen was unnecessary. One patient required concomitant medication to counter the adverse effects. The cure rate was 100%.nnnCONCLUSIONSnThe overall incidence of adverse effects related to the new treatment regimen recommended by the Brazilian Ministry of Health was high. However, none of those effects demanded a change in the regimen, which was effective in the patients evaluated.

Tratamento supervisionado em pacientes portadores de tuberculose utilizando supervisores domiciliares em Vitória, Brasil

OBJETIVO: Avaliar a utilizacao de supervisores domiciliares para dose supervisionada do tratamento(DOT), em pacientes portadores de tuberculose. METODOS: Trata-se de um estudo descritivo prospectivo com amostra composta por pacientes com diagnostico de tuberculose pulmonar. Participaram deste estudo 98 pacientes. Um protocolo de capacitacao do paciente e sua familia foi implementado. Apos este treinamento, o paciente poderia escolher entre um supervisor domiciliar e um profissional de saude. Os metodos de analise descritiva utilizados foram a frequencia absoluta e relativa. RESULTADOS: Um supervisor familiar foi escolhido por 94 pacientes (96%). O percentual de cura foi de 99%. O parceiro foi escolhido por 49% e algum outro familiar o foi por 28% dos pacientes. A equipe de pesquisa precisou assumir o DOT em 3% dos casos. O comparecimento regular para a supervisao foi de 67%. Verificou-se que 24% dos problemas encontrados neste modelo de DOT referiram-se ao esquecimento em administrar ou tomar as medicacoes, por parte do supervisor e do paciente, respectivamente, sendo que 39% dos pacientes deixaram de tomar a medicacao por um dia e 31% esqueceram-se de toma-la por dois dias durante o tratamento. Houve troca de supervisor em 9% da amostra, perda de medicacao pelo paciente em algum momento do tratamento em 9% e intolerância do paciente a medicacao em 8%. CONCLUSOES: O DOT supervisionado pelo familiar mostrou-se eficaz e de baixo custo. No entanto, a adesao ao tratamento nao de deve a um so fator, mas ao conjunto de medidas adotadas: vale transporte; acoes educativas; e, principalmente, a abordagem individualizada.